title: Increased warfarin consumption and residual fibrin turnover in thrombotic patients with primary antiphospholipid syndrome.
abstract: BACKGROUND
  Anedoctal reports suggest that some thrombotic primary antiphospholipid antibody syndrome (PAPS) patients on oral anticoagulation require higher than average doses to achieve given targets international normalized ratios (INR).
  
  
  METHODS
  To test the hypothesis of relative warfarin resistance in thrombotic PAPS and the effect of baseline IgG anticardiolipin antibodies, the cytochrome CYP2C9 and the vitamin K epoxide reductase (VKORC1) haplotypes we compared weekly warfarin consumption of 40 TPAPS (mean age 44 ± 16years) with that of 65 thrombotic patients with inherited thrombophilia (IT) (mean age 52 ± 18) at similar target INR 2.0-3.0 followed up between January-1994 and January 2003. To investigate an involvement of the epoxidation pathway in this difference and to assess enhanced residual fibrin turnover decarboxylated prothrombin (PIVKA-II) and D-dimers (DD) were cross-sectionally investigated in the same patients between March and May 2008.
  
  
  RESULTS
  CEX7 and VKORC1 polymorphisms explained 45.1% of the variability in warfarin consumption, whose age-adjusted mean weekly consumption was greater in PAPS than IT (27.62 vs 21.24 mg, p = 0.03). In PAPS baseline IgG aCL and VKORC1 predicted weekly warfarin consumption (p = 0.028 and p = 0.024). IgG β(2)GPI and warfarin dose independently predicted plasma PIVKA-II (p = 0.01 and p = 0.02). Age and sex adjusted DD was greater in PAPS than IT (132 ± 34 vs 83 ± 37 mg/dl, p = 0.03).
  
  
  CONCLUSIONS
  Thrombotic PAPS exhibit a degree of warfarin resistance partly accounted by antiphospholipid antibodies and are in a state of enhanced fibrin turnover despite oral anticoagulation that might have implications for re-thrombosis and atherosclerosis.
authors.affiliation: Haematology & Rheumatology Departments, Airedale Hospital, Steeton, UK. paxmes@aol.com
authors.forename: Paul R J
authors.initials: PR
authors.lastname: Ames
authors.forename: Maurizio
authors.initials: M
authors.lastname: Margaglione
authors.forename: Antonio
authors.initials: A
authors.lastname: Ciampa
authors.forename: Donatella
authors.initials: D
authors.lastname: Colaizzo
authors.forename: Felicetto
authors.initials: F
authors.lastname: Ferrara
authors.forename: Luigi
authors.initials: L
authors.lastname: Iannaccone
authors.lastname: Vincenzobrancaccio
mesh_terms: D000284:Administration, Oral; D000328:Adult; D017152:Antibodies, Antiphospholipid / Q000097:blood*; D000925:Anticoagulants / Q000008:administration & dosage*; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D005337:Fibrin / Q000378:metabolism*; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D017152:Antibodies, Antiphospholipid; D000925:Anticoagulants; D014859:Warfarin; D005337:Fibrin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases